Total Synthesis of Pseudomonas aeruginosa 1244 Pilin Glycan via de Novo Synthesis of Pseudaminic Acid

Pseudaminic acid (Pse) is a nonulos­onic acid unique to bacterial species, found as a component of important cell surface glycans and glyco­proteins in various pathogenic species, such as the critical hospital threat Pseudomonas aeruginosa. Herein we present the development of a facile and scalable de novo synthesis of Pse and its functionalized derivatives from easily available Cbz-l-allo-threonine methyl ester (16 steps in 11% yield). The key reactions in our de novo synthesis involve the diastereo­selective glycine thioester isonitrile-based aldol-type reaction to create the 1,3-anti-diamino skeleton, followed by the Fukuyama reduction and the indium-mediated Barbier-type allylation. Moreover, we have studied the glycosyl­ation of the Pse glycosyl donors and identified the structural determinants for its glycosyl­ation diastereo­selectivity, which enabled us to complete the total synthesis of P. aeruginosa 1244 pilin trisaccharide α-5NβOHC4­7NFm­Pse-(2→4)-β-Xyl-(1→3)-FucNAc.